Reduction of the ATPase inhibitory factor 1 (IF1) leads to visual impairment in vertebrates

In vertebrates, mitochondria are tightly preserved energy producing organelles, which sustain nervous system development and function. The understanding of proteins that regulate their homoeostasis in complex animals is therefore critical and doing so via means of systemic analysis pivotal to inform pathophysiological conditions associated with mitochondrial deficiency. With the goal to decipher the role of the ATPase inhibitory factor 1 (IF1) in brain development, we employed the zebrafish as elected model reporting that the Atpif1a−/− zebrafish mutant, pinotage (pnttq209), which lacks one of the two IF1 paralogous, exhibits visual impairment alongside increased apoptotic bodies and neuroinflammation in both brain and retina. This associates with increased processing of the dynamin-like GTPase optic atrophy 1 (OPA1), whose ablation is a direct cause of inherited optic atrophy. Defects in vision associated with the processing of OPA1 are specular in Atpif1−/− mice thus confirming a regulatory axis, which interlinks IF1 and OPA1 in the definition of mitochondrial fitness and specialised brain functions. This study unveils a functional relay between IF1 and OPA1 in central nervous system besides representing an example of how the zebrafish model could be harnessed to infer the activity of mitochondrial proteins during development

Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease)

The neuronal ceroid lipofuscinoses are a group of lysosomal storage disorders that comprise the most common, genetically heterogeneous, fatal neurodegenerative disorders of children. They are characterised by childhood onset, visual failure, epileptic seizures, psychomotor retardation and dementia. CLN3 disease, also known as Batten disease, is caused by autosomal recessive mutations in the CLN3 gene, 80–85% of which are a ~1 kb deletion. Currently no treatments exist, and after much suffering, the disease inevitably results in premature death. The aim of this study was to generate a zebrafish model of CLN3 disease using antisense morpholino injection, and characterise the pathological and functional consequences of Cln3 deficiency, thereby providing a tool for future drug discovery. The model was shown to faithfully recapitulate the pathological signs of CLN3 disease, including reduced survival, neuronal loss, retinopathy, axonopathy, loss of motor function, lysosomal storage of subunit c of mitochondrial ATP synthase, and epileptic seizures, albeit with an earlier onset and faster progression than the human disease. Our study provides proof of principle that the advantages of the zebrafish over other model systems can be utilised to further our understanding of the pathogenesis of CLN3 disease and accelerate drug discovery

Update of variants identified in the pancreatic β-cell K ATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes

The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β-cell ATP-sensitive potassium channel, a key component of the glucose-stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.This article is freely available via Open Access. Click on the publisher URL to access it via the publisher's site.P30 DK020595/NH/NIH HHS/United States K23 DK094866/NH/NIH HHS/United States R03 DK103096/NH/NIH HHS/United States 1-11-CT-41/American Diabetes Association/International R01 DK104942/DK/NIDDK NIH HHS/United States WT_/Wellcome Trust/United Kingdom WT098395/Z/12/Z/WT_/Wellcome Trust/United Kingdom UL1 TR000430/NH/NIH HHS/United States P30 DK020595/DK/NIDDK NIH HHS/United States UL1 TR000430/TR/NCATS NIH HHS/United States 1-17-JDF-008/American Diabetes Association/International 105636/Z/14/Z/WT_/Wellcome Trust/United Kingdom 110675/European Association for the Study of Diabetes-Novo Nordisk/International 16/0005407/DUK_/Diabetes UK/United Kingdom R01 DK104942/NH/NIH HHS/United States R03 DK103096/DK/NIDDK NIH HHS/United States K23 DK094866/DK/NIDDK NIH HHS/United Statespublished version, accepted version (12 month embargo), submitted versio

Svestka's Research: Then and Now

Zdenek Svestka's research work influenced many fields of solar physics, especially in the area of flare research. In this article I take five of the areas that particularly interested him and assess them in a "then and now" style. His insights in each case were quite sound, although of course in the modern era we have learned things that he could not readily have envisioned. His own views about his research life have been published recently in this journal, to which he contributed so much, and his memoir contains much additional scientific and personal information (Svestka, 2010).Comment: Invited review for "Solar and Stellar Flares," a conference in honour of Prof. Zden\v{e}k \v{S}vestka, Prague, June 23-27, 2014. This is a contribution to a Topical Issue in Solar Physics, based on the presentations at this meeting (Editors Lyndsay Fletcher and Petr Heinzel

Comparison of intima-media thickness and ophthalmic artery resistance index for assessing subclinical atherosclerosis in HIV-1-infected patients

<p>Abstract</p> <p>Background</p> <p>Human immunodeficiency virus (HIV) infection and antiretroviral treatment are associated with metabolic and cardiovascular complications that potentially increase the risk of atherosclerosis and cardiovascular disease in this population. Measurement of arterial wall thickness has been used as a surrogate of extent, severity and progression of atherosclerosis. A cross-sectional cohort study was performed to compare the validity of two non-invasive arterial measures: carotid intima-media thickness (IMT), a parameter of atherosclerosis, and ophthalmic artery resistance index (OARI), an index of occlusive carotid artery disease.</p> <p>Methods</p> <p>A total of 95 patients receiving highly active antiretroviral therapy (HAART) for more than 12 months were consecutively enrolled. IMT and OARI were measured by 7.5 MHz linear probe.</p> <p>Results</p> <p>There was a significant linear increase in IMT and OARI values as the grade of cardiovascular risk (0.70 and 0.69 for very low risk, 0.86 and 0.72 for low risk and 0.98 and 0.74 for medium/high risk, p < 0.001). A IMT > 0.83 and an OARI > 0.72 were the most discriminatory values for predicting a cardiovascular risk ≥ 10% (sensibility 89.6% and 75.8%; sensitivity 70.5% and 68.4%; p < 0.001).</p> <p>Conclusions</p> <p>Our data indicate that OARI may have a potential as a new precocious marker of subclinical atherosclerosis in HIV-1-infected patients.</p

Ultrasound-assessed perirenal fat is related to increased ophthalmic artery resistance index in HIV-1 patients

<p>Abstract</p> <p>Background</p> <p>The introduction of highly active antiretroviral therapy (HAART) has dramatically changed the prognosis of human immunodeficiency virus (HIV) infection, with a significant decline in morbidity and mortality.</p> <p>Changes in body fat distribution are a common finding in individuals with HIV infection being treated with antiretrovirals, and this condition (collectively termed lipodystrophy syndrome) is associated with depletion of subcutaneous fat, increased triglycerides and insulin resistance. Obesity, particularly visceral obesity, is associated with increased risk of cardiovascular disease. Therefore, estimating visceral fat distribution is important in identifying subjects at high risk for cardiovascular disease.</p> <p>The aim of our study was to evaluate whether perirenal fat thickness (PRFT), a parameter of central obesity, is related to ophthalmic artery resistance index (OARI), an index of occlusive carotid artery disease in HIV-1 infected patients.</p> <p>Methods</p> <p>We enrolled 88 consecutive HIV-1-infected patients receiving highly active antiretroviral therapy for more than 12 months, in a prospective cohort study. Echographically measured PRFT and OARI, as well as serum metabolic parameters, were evaluated. PRFT and OARI were measured by 3.75 MHz convex and 7.5 MHz linear probe, respectively.</p> <p>Results</p> <p>The means of PRFT and OARI in HIV-1-infected patients with visceral obesity was considerably higher than in patients without it (p < 0.0001 and p < 0.001, respectively). Using the average OARI as the dependent variable, total serum cholesterol level, HDL, triglycerides, glycemia, sex, blood pressure, age and PRFT were independent factors associated with OARI. A PRFT of 6.1 mm was the most discriminatory value for predicting an OARI > 0.74 (sensitivity 78.9%, specificity 82.8%).</p> <p>Conclusions</p> <p>Our data indicate that ultrasound assessment of PRFT may have potential as a marker of increased endothelial damage with specific involvement of the ocular vascular region in HIV-1-infected patients.</p

A Plasma Metabolomic Signature of the Exfoliation Syndrome Involves Amino Acids, Acylcarnitines, and Polyamines

Purpose: To determine the plasma metabolomic signature of the exfoliative syndrome (XFS), the most common cause worldwide of secondary open-angle glaucoma. Methods: We performed a targeted metabolomic study, using the standardized p180 Biocrates Absolute IDQ p180 kit with a QTRAP 5500 mass spectrometer, to compare the metabolomic profiles of plasma from individuals with XFS (n = 16), and an age- and sex-matched control group with cataract (n = 18). Results: A total of 151 metabolites were detected correctly, 16 of which allowed for construction of an OPLS-DA model with a good predictive capability (Q2cum = 0.51) associated with a low risk of over-fitting (permQ2 = -0.48, CV-ANOVA P-value &lt;0.001). The metabolites contributing the most to the signature were octanoyl-carnitine (C8) and decanoyl-carnitine (C10), the branched-chain amino acids (i.e., isoleucine, leucine, and valine), and tyrosine, all of which were at higher concentrations in the XFS group, whereas spermine and spermidine, together with their precursor acetyl-ornithine, were at lower concentrations than in the control group. Conclusions: We identified a significant metabolomic signature in the plasma of individuals with XFS. Paradoxically, this signature, characterized by lower concentrations of the neuroprotective spermine and spermidine polyamines than in controls, partially overlaps the plasma metabolomic profile associated with insulin resistance, despite the absence of evidence of insulin resistance in XFS

Search for CP Violation in the Decay Z -> b (b bar) g

About three million hadronic decays of the Z collected by ALEPH in the years 1991-1994 are used to search for anomalous CP violation beyond the Standard Model in the decay Z -> b \bar{b} g. The study is performed by analyzing angular correlations between the two quarks and the gluon in three-jet events and by measuring the differential two-jet rate. No signal of CP violation is found. For the combinations of anomalous CP violating couplings, ${\hat{h}}_b = {\hat{h}}_{Ab}g_{Vb}-{\hat{h}}_{Vb}g_{Ab}$ and $h^{\ast}_b = \sqrt{\hat{h}_{Vb}^{2}+\hat{h}_{Ab}^{2}}$, limits of \hat{h}_b < 0.59$and$h^{\ast}_{b} < 3.02$ are given at 95\% CL.Comment: 8 pages, 1 postscript figure, uses here.sty, epsfig.st

Tracking positive and negative effects of inequality on long-run growth

Despite extensive research controversy remains on the effects of income inequality on economic growth. The literature proposes several transmission channels through which these effects may occur and even the existence of two different forms of inequality. However, empirical studies have not generally distinguished between these channels, nor have they considered the two forms of inequality and their separate effects on growth. In this paper we review the theory and the evidence of the transmission channels through which inequality influences growth. We contribute to the literature by using a system of recursive equations, following a control function approach, to empirically assess the relevance of these channels and to differentiate between two forms of inequality. In a single model, we capture both a negative and a positive effect of inequality on long-run economic growt